DESCRIPTION: The prefrontal cortex (PFC) plays important roles in cognitive and affective function. Dysfunction within PFC circuitry is strongly implicated in the pathophysiology of schizophrenia, particularly in the expression of negative symptoms. The ability of atypical antipsychotics such as clozapine to ameliorate these negative symptoms has focused attention on the serotonin (5-HT) as well as dopamine (DA) modulatory systems within the PFC, as these drugs are potent antagonists at both 5-HT and DA receptors. Despite the importance of these two neuromodulatory systems in regulating PFC neuronal activity, very little is known as to how they affect the ionic conductances that shape information processing within PFC cells. Moreover, almost nothing is known as to how 5-HT and DA interact at the level of individual PFC neurons. To address these issues, a research and training plan is proposed utilizing a combination of electrophysiological, pharmacological and molecular biological techniques to achieve two specific aims. The first is to examine the effect of 5-HT2a/c receptor stimulation on Na+ currents in acutely isolated PFC neurons and to characterize the mediating signaling cascade. The second aim is to characterize the nature and mechanism of interaction of 5-HT2a/c and DA1/5 signaling pathways on Na+ currents will be examined. The achievement of these aims will provide vital information necessary to construct accurate, integrative models of PFC function as well as dysfunctional states such as schizophrenia.